(1) Field of Invention
The present invention related to certain novel N-(aryl-, aryloxy-, arylthio-, arylsulfinyl- and arylsulfonyl-)alkyl-N,N'-(or N',N')alkylaminoalkyl ureas, thioureas and cyanoguanidines and the pharmaceutically acceptable acid addition salts and hydrate thereof, and pharmaceutical processes and compositions for administering the same to a living animal body for its cardiac antiarrhythmic effect.
(2) Information Disclosure Statement
Procainamide hydrochloride (4-amino-N-[2-(diethylamino)ethyl]benzamide monohydrochloride), has been used in the art to suppress certain cardiac arrhythmias.
Recently, Protiva, M. et al. have disclosed in Czeck Patent 146,873 [C.A. 79, 42205g] compounds such as m-ClC.sub.6 H.sub.4 O(CH.sub.2).sub.3 CONH(CH.sub.2).sub.2 N(C.sub.2 H.sub.5).sub.2 useful for lowering blood sugar levels in rats.
Joullie M. et al., in U.S. Pat. No. 4,252,804 have disclosed 3,4,5-trimethoxybenzene derivatives which have the general structure (CH.sub.3 O).sub.3 --C.sub.6 H.sub.2 --X--(CH.sub.2).sub.m --Y--(CH.sub.2).sub.m --NR.sub.1 R.sub.2 wherein; X is oxygen or ##STR2## (wherein R.sub.3 represents a hydrogen atom, benzyl or mopholinoethyl group); Y represents one of the divalent groups Co, CONH, COO or SO.sub.2 and NR.sub.1 R.sub.2 can be selected from a list of possible values among which are dimethylaminopropylamino or N-methyl-N-dimethylaminopropylamino. These compounds are disclosed to be useful as myorelaxants, anticonvulsants and tranquilizers.
Koelzer, P. P. and Wehr, K. H. in Arzneim. Forsch 9, 113-120 (1959) disclosed two unsubstituted phenoxy urea compounds; namely,
N'-[2-(diethylamino)ethyl]-N-methyl-N-[2-(phenoxy)ethyl]urea and
N-methyl-N-[2-(phenoxy)ethyl]-N'-[2-(pyrrolidinyl)ethyl]urea. Anesthetic activity in animals was disclosed but clinical use of these ureas was said to be unlikely. There is no disclosure of thiourea compounds.
Certain N-(aryloxyalkyl)-N'-(aminoalkyl)ureas and thioureas are disclosed in U.S. Pat. Nos. 4,500,529 and 4,558,155 to have antiarrhythmic properties and have the general formula: ##STR3## Wherein;
R.sup.1 and R.sup.2 are selected from the group consisting of hydrogen, loweralkyl, cycloalkyl, phenyl, phenyl substituted by halogen, loweralkyl or loweralkoxy or phenylloweralkyl and loweralkoxy, R.sup.3 and R.sup.4 are selected from the groups consisting of hydrogen, loweralkyl, loweralkoxy and phenylloweralkyl wherein phenyl may be substituted by halogen, loweralkyl, loweralkoxy, and R.sup.3 and R.sup.4 may be taken together with the adjacent nitrogen to form a heterocyclic residue, X is selected from oxygen or sulfur, Ar is selected from 1 and 2 naphthyl, 2,3-dihydro-1H-inden-4(or 5)-yl, 3-pyridinyl, phenyl or substituted phenyl, and alk.sup.1 and alk.sup.2 are selected from the group consisting of loweralkylene or loweralkylene-loweralkyl.
Certain N-(arylthioalkyl)-N'-(aminoalkyl)ureas and thioureas are diclosed in U.S. Pat. No. 4,597,902 to have a high degree of cardiac activity in animals which compounds have the structure: ##STR4## wherein B is thio, sulfinyl or sulonyl; R.sup.1 and R.sup.2 are hydrogen, loweralkyl, cycloalkyl, 2-furanyl, phenyl, phenylloweralkyl and substituted phenyl; R.sup.3 and R.sup.4 are hydrogen, loweralkyl, phenyl, phenylloweralkyl and substituted phenyl or R.sup.3 and R.sup.4 with adjacent nitrogen form a heterocyclic residue.